We have succeeded in reducing chronic nociception in rats by long-term upregulation of mu-opioid receptors (MORs) in sensory neurons. Now we want to develop similar viral-vector-mediated therapy for use in humans. Chronic pain is one of the worst human ailments. According to the National Pain Foundation, more than 75 million Americans live with chronic pain. It is the primary reason for physician visits. Medications and loss of productivity cost $120 billion dollars a year in the US. The price in physical and emotional suffering of patients is incalculable. Opiates, such as morphine, are still the most effective and widely used drugs for treatment of severe pain. However, their side effects, e.g., tolerance, withdrawal and respiration depression, often lead to discontinuation of treatment. Recently, we successfully designed an efficient strategy to improve opioid analgesia. We upregulate MOR expression in primary sensory neurons using a recombinant adeno-associated viral vector, i.e., rAAV2-MOR. This manipulation greatly increases the analgesic effects of morphine in rats with chronic inflammation and nerve injury. To make the vector feasible for clinical and commercial use, our Phase 1 goals are (i) to improve the transduction efficiency of target genes using the AAV8 serotype and (ii) to assess the immune responses to rAAV8-MOR. If Phase I data indicate feasibility, we will, in Phase II, conduct safety and efficacy studies in sheep. If successful, we will conduct a small scale safety study (FDA Phase I) in humans with chronic pain. Several pharmaceutical partners have already expressed interest in licensing our technology to conduct the FDA Phase II and III trials and to bring the product to market. [unreadable] [unreadable] [unreadable]